Carcinogenesis, Vol 19, 1231-1237, Copyright © 1998 by Oxford University Press
P Lennartsson, J Hogberg and U Stenius
Previous reports have documented an attenuated p53 response to DNA damage
in hepatocytes isolated from enzyme-altered foci (EAF). Here, we have
studied this p53 response in vivo in rats with EAF. These animals received
repeated doses of diethylnitrosamine (DEN) for 6 weeks and a challenging
dose 24 h before death. Liver sections were then analysed using an
immunohistological procedure for p53, or a double-staining procedure for
p53 and glutathione-S-transferase pi (GST-P). In control rats or rats with
EAF not given the challenging dose of DEN, there was no p53 staining. In
control rats, only given the challenging dose of DEN, there was a
centrilobular p53 nuclear staining that co-localized with TUNEL staining.
In an experiment involving four rats with EAF 389 +/- 39 hepatocytes/mm2 of
non-EAF tissue stained positively for p53, while the corresponding value
for EAF tissue was 27.6 +/- 7.5. Thus, p53-positive cells were 14.6-fold
more frequent in non-EAF than in EAF tissue. In many EAF no p53-positive
cells were seen at all and 83% of the EAF demonstrated <20% of the
number of p53-positive cells seen in non-EAF tissue. Very few EAF had as
high a proportion of p53-positive cells as did the average non-EAF tissue.
EAF >0.06 mm2 had significantly fewer p53-positive cells than smaller
EAF. The ratio of p53 expression in non-EAF tissue and large EAF was 32.6.
In a control experiment, four EAF-bearing rats were used as donors to
prepare primary cultures of hepatocytes. After 24 h of exposure to DEN,
many of the cultured cells became p53-positive. Among GST-P-negative
hepatocytes, 12.8% were p53-positive, whereas only 0.25% of the GST-P-
positive hepatocytes were p53-positive. Literature data suggest that the
altered xenobiotic metabolism in EAF may give rise to a 3-4-fold difference
in DNA damage between non-EAF and EAF tissues. It is concluded that
GST-P-positive EAF hepatocytes have an attenuated p53 response to DNA
damage. This attenuated response may facilitate clonal expansion of EAF
under stress induced by DNA-damaging chemicals.
ARTICLES
Wild-type p53 expression in liver tissue and in enzyme-altered foci: an in vivo investigation on diethylnitrosamine-treated rats
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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